Recent genome-wide association studies have shown that genetic polymorphisms in the interferon-lambda gene are highly associated with viral clearance and treatment response. Furthermore variations in the inosine triphosphate pyrophosphatase (ITPA) gene have also been closely linked to ribavirin-induced anemia in other GWAS studies. We are genotyping our patient populations to further explore this genetic linkage and understand the functional relationship of these associations. Hepatitis C virus (HCV) infection leads to activation of a cellular innate immune response and production of antiviral interferon stimulated genes (ISGs). Persistently high expression of ISGs is associated with poor response to interferon-based treatment. How rapidly ISGs are downregulated and whether they play a role in eradication of HCV during DAA therapy is unknown. To investigate the effects of DAA therapy on ISG expression in patients with chronic HCV infection and whether innate immunity is involved in HCV clearance during DAA therapy. Subjects who had previously failed a course of peginterferon/ribavirin were re-treated with asunaprevir/daclatasvir for 24 weeks. Following pre-treatment biopsy, patients were randomized to undergo a second biopsy at week 2 or 4 on-therapy. Microarray analysis was performed on paired liver biopsies using linear mixed models. Phenotypic and functional characterization of natural killer (NK) cells from peripheral blood were performed using TRAIL and pSTAT1 staining and NK cell degranulation. 11 patients with HCV genotype 1b infection were studied. The sustained virological response (SVR12) rate was 64% (7/11). All 4 failures experienced virological breakthrough between weeks 4-12. Comparing gene expression levels from on-therapy biopsies to baseline, 386 genes (1.2 fold, p<0.01) were differentially expressed. Genes downregulated on treatment were predominantly ISGs. Downregulation of ISGs was rapid and correlated with HCV RNA suppression. Patients who achieved SVR12 had higher pre-treatment ISG expression and a higher frequency of NK cell pSTAT1 staining, NK cell degranulation and TRAIL expression compared to those who experienced virological relapse.